| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 2041321 | Cell Reports | 2014 | 7 Pages |
•Modeling shows negative-feedback regulation enhances mutational robustness•Negative feedback rescues expression, function, and survival of mutants•Negative-feedback transcription-factor sequences are diverging rapidly
SummaryNatural selection for specific functions places limits upon the amino acid substitutions a protein can accept. Mechanisms that expand the range of tolerable amino acid substitutions include chaperones that can rescue destabilized proteins and additional stability-enhancing substitutions. Here, we present an alternative mechanism that is simple and uses a frequently encountered network motif. Computational and experimental evidence shows that the self-correcting, negative-feedback gene regulation motif increases repressor expression in response to deleterious mutations and thereby precisely restores repression of a target gene. Furthermore, this ability to rescue repressor function is observable across the Eubacteria kingdom through the greater accumulation of amino acid substitutions in negative-feedback transcription factors compared to genes they control. We propose that negative feedback represents a self-contained genetic canalization mechanism that preserves phenotype while permitting access to a wider range of functional genotypes.
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